In this proposal, we aim to use a systems biology approach to survey immune responsiveness across a range of different vaccines including influenza, both seasonal and the new pandemic H1N1v, Herpes zoster, Measles, and the bacterium Neisseria meningitidis. In the case of influenza and Herpes zoster, we will also be able to directly compare the immune response to vaccines with those natural responses to the pathogen itself. These investigations will compare different age groups-children, young adults, and the elderly-to look for specific markers and assays of immune competence and especially those that might be common across different pathogens and age groups. We will also survey the influenza vaccine responses of individuals with impaired or dysregulated immune systems in order to see how these might deviate from healthy individuals. We will employ a streamlined model in which clinical specimens from individuals exposed to different vaccines or infectious diseases will all be assayed for an array of basic immune functions in our Human Immune Monitoring Center and also for several state of the art assays such as our recently developed high throughput HLA sequencing technique, which is able to generate complete HLA haplotypes from hundreds of people simultaneously. We will also perform selected Immunoglobulin and T Cell Receptor repertoire analysis and combinatorial peptide-MHC tetramer analysis to efficiently search for informative T cell epitopes. We will employ advanced bioinformatics analysis such as our new cell type specific SAM algorithms (csSAM), which use cell subset information to achieve much higher sensitivity from whole blood gene expression data as well as developing new bioinformatics tools to interrogate our rich and complex data base across all projects, pilots and cores.